This application is a 371 of PCT/JP99/02631 filed May 19, 1999.
The present invention relates to a novel hydroxamic acid derivative and a pharmacologically acceptable salt thereof. More particularly, the present invention relates to a hydroxamic acid derivative or a pharmacologically acceptable salt thereof, which are useful as an inhibitor of TNF xcex1 (tumor necrosis factor xcex1) production. The present invention also relates to a novel intermediate compound useful for the synthesis of the above-mentioned hydroxamic acid derivative.
TNF xcex1 is a cytokine known to be widely involved in the activation of biological defense and immune system during inflammation. On the other hand, it is known that a sustained and excessive production of TNF xcex1 causes various diseases associated with organ disorders represented by MOF (multiple organ failure), as well as aggravation thereof.
MOF is understood to be a functional failure that simultaneously or continuously emerges in-plural important organs, such as lung, heart, kidney, liver, central nervous system, blood coagulation system and the like, during progress of a major invasion (after major operation, after serious external injuries, burn, acute pancreatitis, severe infection and the like). MOF shows poor prognosis, which is in proportion to the number of dysfunctional organs, and an extremely high mortality.
Nevertheless, it is a representative intractable disease for which no cure has been established.
In recent years, a report has documented that an inhibitor of MMP (matrix metalloproteinase), which is an enzyme in charge of processing from membrane-bound TNF xcex1 to free TNF xcex1, specifically suppresses the secretion of free TNF xcex1, which is caused by the stimulation of endotoxin (LPS:lipopolysaccharide), and shows a life-saving effect [e.g., McGeehan, G. M. et al. Nature 370: p. 558-561 (1994)].
Given such finding, a wide range of investigations of prophylactic and therapeutic agents for various intractable diseases, inclusive of MOF where free TNF xcex1 increases, have been underway by inhibiting TNF xcex1 production by the use of a hydroxamic acid derivative that has heretofore been studied as an MMP inhibitor (e.g., WO94/10990). However, a satisfactory prophylactic and therapeutic agent has not been afforded.
The present invention has been made in the above-mentioned background and aims at providing a novel hydroxamic acid derivative or a pharmacologically acceptable salt thereof, which is useful as an inhibitor of TNF xcex1 production.
It is another object of the present invention to provide a novel intermediate compound useful for the synthesis of said compound.
A further object of the present invention is to provide a novel inhibitor of TNF xcex1 production, which is useful as a pharmaceutical agent.
Accordingly, the present invention provides the following (1) to (11).
(1) A hydroxamic acid derivative of the formula (I): 
wherein
X is hydrogen or hydroxy-protecting group;
R1 is hydrogen, alkyl, arylalkyl, heteroarylthioalkyl, arylthioalkyl, alkylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, alkenyl, or xe2x80x94(CH2)lxe2x80x94A
wherein l is an integer of 1 to 4 and A is a 5- or 6-membered N-heterocycle
(a) which is bonded by N atom,
(b) which optionally has at least one atom selected from N, O and S as an additional heteroatom at a position not adjacent to the bonded N atom,
(c) in which one or both C atom(s) adjacent to said bonded N atom is(are) substituted by oxo, and
(d) which is benzo-fused, or one or more other C atom(s) is(are) substituted by lower alkyl or oxo, and/or a different N atom is optionally substituted by lower alkyl or phenyl;
R2 is hydrogen, alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or aryl;
R3 is hydrogen, alkyl or a group of the formula 
wherein Q1 is an aromatic hydrocarbon ring or an aromatic heterocycle, m is an integer of 0 to 3, and R is hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, alkoxy, alkylthio, formyl, acyloxy, phenyl, arylalkyl, carboxy, xe2x80x94COORa wherein Ra is lower alkyl, arylalkyl or aryl, carbamoyl, guanidino, hydroxysulfonyloxy, sulfo, arylalkyloxyalkyl or a group selected from 
wherein n and q are the same or different and each is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, R16 is aryl, heteroaryl, hydroxysulfonyloxy or sulfo and R17 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy; and
Y is a group of the formula 
wherein Q2 is an aromatic hydrocarbon ring or an aromatic heterocycle, and R1 is hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, alkoxy, alkylthio, formyl, acyloxy, phenyl, arylalkyl, carboxy, xe2x80x94COORa wherein Ra is lower alkyl, arylalkyl or aryl, carbamoyl, guanidino, hydroxysulfonyloxy, sulfo, arylalkyloxyalkyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, R21 is aryl, heteroaryl, hydroxysulfonyloxy, sulfo or carboxy, and R22 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy;
provided that
(i) R3 is a group of the formula (A) 
wherein Q1 is a benzene ring, m is an integer of 0 to 3, and R13 is guanidino, hydroxysulfonyloxy, sulfo or a group selected from 
wherein n is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R16 is hydroxysulfonyloxy or sulfo, or
(ii) when R3 is a group other than the aforementioned formula (A),
Y should be a group of the formula (B) 
wherein Q2 is a benzene ring, and R18 is a group selected from 
wherein s is an integer of 1 to 5, u is an integer of 1 or 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R21 is aryl, heteroaryl, hydroxysulfonyloxy, sulfo or carboxy, or
Q2 is a furan ring, and R18 is arylalkyloxyalkyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R22 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy,
wherein the aforementioned arylalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, aryl, heteroaryl and heteroarylalkyl may have a substituent, or a pharmacologically acceptable salt thereof.
(2) The hydroxamic acid derivative of the aforementioned (1) wherein
(i) R3 is a group of the formula (A) 
wherein Q1 is a benzene ring, m is an integer of 0 to 3, and R13 is guanidino, hydroxysulfonyloxy, sulfo or a group selected from 
wherein n is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R16 is hydroxysulfonyloxy or sulfo, and
Y is furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, phenyl, alkoxyphenyl, or phenyl substituted by xe2x80x94NR19R20 
wherein R19 and R20 are the same or different and each is alkyl, or
(ii) R3 is alkyl or a group of the formula 
wherein Q1 is a benzene ring, m is an integer of 0 to 3, and R13 is hydrogen, and
Y is a group of the formula (B) 
wherein Q2 is a benzene ring, and R18 is a group selected from 
wherein s is an integer of 1 to 5, u is an integer of 1 or 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R21 is aryl, heteroaryl, hydroxysulfonyloxy, sulfo or carboxy, or
Q2 is a furan ring, and R18 is arylalkyloxyalkyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R22 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy,
or a pharmacologically acceptable salt thereof.
(3) The hydroxamic acid derivative of the aforementioned (2), wherein R13 in the formula (A) is guanidino, hydroxysulfonyloxy or a group of the formula 
wherein each symbol is as defined in the aforementioned (2) or a pharmacologically acceptable salt thereof.
(4) The hydroxamic acid derivative of the aforementioned (2) or a pharmacologically acceptable salt thereof, which is a member selected from the group consisting of
5-methyl-3(R)-[1(S)-[4-[2-[1-(4-methyl)piperazinyl]ethoxy]benzoyl]-2-phenyl]ethylcarbamoyl-2(R or S)-phthalimidomethylhexanohydroxamic acid dihydrochloride,
3(R)-[1(S)-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid hydrochloride,
3(R)-[1(S)-(2-furyl)carbonyl-2-(4-guanidinophenyl)]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid hydrochloride,
3(R)-[1(S)-[2-[5-(2-dimethylaminoethoxy)methyl]furyl]carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid hydrochloride,
3(R)-[2-[4-(2-dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic acid hydrochloride,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(2-naphthylmethyl)hexanohydroxamic acid,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(1-naphthylmethyl)hexanohydroxamic acid,
sodium salt of 2(R or S)-benzyl-3(R)-[1(S)-(2-furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methylhexanohydroxamic acid,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-(4-sulfophenyl)-ethylcarbamoyl]-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(1-oxoisoindolin-2-ylmethyl)hexanohydroxamic acid,
3(R)-[2-(4-aminophenyl)-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid hydrochloride,
5-methyl-3(R)-[2-phenyl-1(S)-[4-(2-piperidinoethoxy)benzoyl]]ethylcarbamoyl-2(R or S)-phthalimidomethylhexanohydroxamic acid hydrochloride,
3(R)-[1(S)-[2-(5-dimethylaminomethyl)furyl]carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid hydrochloride,
3(R)-[2-[4-(2-dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid hydrochloride,
3(R)-[1(S)-[2-(5-hydroxymethyl)furyl]carbonyl-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid,
2(R or S),5-dimethyl-3(R)-[1(S)-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoylhexanohydroxamic acid hydrochloride,
3(R)-[1(S)-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(3-phenylpropyl)hexanohydroxamic acid hydrochloride,
3(R)-[1(S)-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic acid hydrochloride,
3(R)-[2,2-dimethyl-1(S)-[4-(2-dimethylaminoethoxy)benzoyl]]propylcarbamoyl-5-methyl-2(R or S)-phthalimidomethylhexanohydroxamic acid hydrochloride,
3(R)-[1(S)-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(2-propenyl)hexanohydroxamic acid hydrochloride,
3(R)-[2-[4-(2-dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(3-phenylpropyl)hexanohydroxamic acid hydrochloride,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic acid,
3(R)-[2,2-dimethyl-1(S)-[4-(2-dimethylaminoethoxy)benzoyl]]propylcarbamoyl-5-methyl-2(R or S)-(3-phenylpropyl)hexanohydroxamic acid hydrochloride,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-(3-phenylpropyl)hexanohydroxamic acid,
3(R)-[1(S)-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(2-naphthylmethyl)hexanohydroxamic acid hydrochloride,
3(R)-[1(S)-[4-(2-dimethylaminoethoxy)benzoyl]-2-phenyl]ethylcarbamoyl-5-methyl-2(R or S)-(1-oxoisoindolin-2-ylmethyl)hexanohydroxamic acid hydrochloride,
3(R)-[2-[4-(2-dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(2-naphthylmethyl)-hexanohydroxamic acid hydrochloride,
3(R)-[2-[4-(2-dimethylaminoethoxy)phenyl]-1(S)-(2-furyl)carbonyl]ethylcarbamoyl-5-methyl-2(R or S)-(1-oxoisoindolin-2-ylmethyl)hexanohydroxamic acid hydrochloride,
3(R)-[2,2-dimethyl-1(S)-[4-(2-dimethylaminoethoxy)benzoyl]]propylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic acid hydrochloride,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-(2-naphthylmethyl)hexanohydroxamic acid,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-[4-(hydroxysulfonyloxy)phenyl]]ethylcarbamoyl-5-methyl-2(R or S)-(1-oxoisoindolin-2-ylmethyl)hexanohydroxamic acid,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(3-phenylpropyl)hexanohydroxamic acid,
sodium salt of 3(R)-[1(S)-(2-furyl)carbonyl-2-(4-sulfophenyl)ethylcarbamoyl]-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic acid, and
3(R)-[1(S)-[2-(5-hydroxymethyl)furyl]carbonyl-2-phenyl]-ethylcarbamoyl-5-methyl-2(R or S)-(2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl)methylhexanohydroxamic acid.
(5) The hydroxamic acid derivative of the aforementioned (1) or (2), wherein R1 is phthalimidomethyl, or a pharmacologically acceptable salt thereof.
(6) The hydroxamic acid derivative of the aforementioned (1) or (2), wherein R2 is isobutyl, or a pharmacologically acceptable salt thereof.
(7) The hydroxamic acid derivative of the aforementioned (1) or (2), wherein R3 is benzyl optionally substituted by a substituent selected from guanidino, hydroxysulfonyloxy, sulfo, 
wherein n is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R16 is hydroxysulfonyloxy or sulfo, or a pharmacologically acceptable salt thereof.
(8) A compound of the formula (II): 
wherein
R11 is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, 
is a single bond or a double bond,
when 
is a single bond, R12 is hydrogen, alkyl, arylalkyl, heteroarylthioalkyl, arylthioalkyl, alkylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, alkenyl, xe2x80x94(CH2)lxe2x80x94A
wherein l is an integer of 1 to 4, A is a 5- or 6-membered N-heterocycle
(a) which is bonded by N atom,
(b) which optionally has at least one atom selected from N, O and S as an additional heteroatom at a position not adjacent to the bonded N atom,
(c) in which one or both C atom(s) adjacent to said bonded N atom is(are) substituted by oxo, and
(d) which is benzo-fused, or one or more other C atom(s) is(are) substituted by lower alkyl or oxo, and/or a different N atom is optionally substituted by lower alkyl or phenyl, or
xe2x80x94COOR23 wherein R23 is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or
when 
is a double bond, R12 is CH2;
R2 is hydrogen, alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or aryl;
R3 is hydrogen, alkyl or a group of the formula 
wherein Q1 is an aromatic hydrocarbon ring or an aromatic heterocycle, m is an integer of 0 to 3, and R13 is hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, alkoxy, alkylthio, formyl, acyloxy, phenyl, arylalkyl, carboxy, xe2x80x94COORa wherein Ra is lower alkyl, arylalkyl or aryl, carbamoyl, guanidino, hydroxysulfonyloxy, sulfo, arylalkyloxyalkyl or a group selected from 
wherein n and q are the same or different and each is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, R16 is aryl, heteroaryl, hydroxysulfonyloxy or sulfo, and R17 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy;
Y is a group of the formula 
wherein Q2 is an aromatic hydrocarbon ring or an aromatic heterocycle, and R18 is hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, alkoxy, alkylthio, formyl, acyloxy, phenyl, arylalkyl, carboxy, xe2x80x94COORa wherein Ra is lower alkyl, arylalkyl or aryl, carbamoyl, guanidino, hydroxysulfonyloxy, sulfo, arylalkyloxyalkyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, R21 is aryl, heteroaryl, hydroxysulfonyloxy, sulfo or carboxy, and R22 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy;
provided that
(i) R3 is a group of the formula (A) 
wherein Q1 is a benzene ring, m is an integer of 0 to 3, and R13 is guanidino, hydroxysulfonyloxy, sulfo or a group selected from 
wherein n is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R16 is hydroxysulfonyloxy or sulfo, or
(ii) when R3 is a group other than the aforementioned formula (A),
Y should be a group of the formula (B) 
wherein Q2 is a benzene ring, and R18 is a group selected from 
wherein s is an integer of 1 to 5, u is an integer of 1 or 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R21 is aryl, heteroaryl, hydroxysulfonyloxy, sulfo or carboxy, or
Q2 is a furan ring, and R18 is arylalkyloxyalkyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R22 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy,
wherein the aforementioned arylalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, aryl, heteroaryl and heteroarylalkyl may have a substituent [hereinafter to be referred to as intermediate compound (II)].
(9) The compound of the aforementioned (8) wherein
(i) R3 is a group of the formula (A) 
wherein Q1 is a benzene ring, m is an integer of 0 to 3, and R13 is guanidino, hydroxysulfonyloxy, sulfo or a group selected from 
wherein n is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R16 is hydroxysulfonyloxy or sulfo, and
Y is furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, phenyl, alkoxyphenyl, or phenyl substituted by xe2x80x94NR19R20 
wherein R19 and R20 are the same or different and each is alkyl, or
(ii) R3 is alkyl or a group of 
wherein Q1 is a benzene ring, m is an integer of 0 to 3, and R13 is hydrogen, and
Y is a group of the formula (B) 
wherein Q2 is a benzene ring, and R18 is a group selected from 
wherein s is an integer of 1 to 5, u is an integer of 1 or 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R21 is aryl, heteroaryl, hydroxysulfonyloxy, sulfo or carboxy, or
Q2 is a furan ring, and R18 is arylalkyloxyalkyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R22 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy.
(10) A pharmaceutical composition comprising a hydroxamic acid derivative of any of the aforementioned (1) to (7) or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.
(11) The pharmaceutical composition of the aforementioned (10), which is an inhibitor of TNF xcex1 production.
The symbols used in the present specification are explained in the following.
The alkyl at R1, R2, R3, R11, R12, R14, R15, R19, R20and R23 may be a linear or branched chain preferably having 1 to 10 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-octyl, n-decyl and the like.
The arylalkyl at R1, R2, R11, R12, R14, R15, R19, R20 and R23 is that wherein the alkyl moiety may be a linear or branched chain preferably having 1 to 6 carbon atoms, and the aryl moiety is preferably a phenyl, naphthyl or ortho-fused bicyclic group having 8 to 10 ring-forming atoms, wherein at least one ring is an aromatic ring (e.g., indenyl and the like). Examples thereof include benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl and the like.
The heteroarylthioalkyl at R1 and R12 is that wherein the alkyl moiety may be a linear or branched chain preferably having 1 to 6 carbon atoms, and the heteroaryl moiety is a 5- or 6-membered cyclic group preferably having a carbon atom and 1 to 4 heteroatoms (e.g., oxygen, sulfur or nitrogen), or an ortho-fused bicyclic heteroaryl derived therefrom, which has 8 to 10 ring-forming atoms, particularly a benzo derivative wherein the heterocycle is fused with benzene ring, or a derivative wherein the heterocycle is fused with propenylene, trimethylene or tetramethylene, a stable N-oxide thereof and the like. Examples of the heteroaryl moiety include pyrrolyl, pyrrolinyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, chromenyl, isoindolyl, indolyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzoxazinyl and the like.
Examples of heteroarylthioalkyl include 2-pyrrolylthiomethyl, 2-pyridylthiomethyl, 3-pyridylthiomethyl, 4-pyridylthiomethyl, 2-thienylthiomethyl and the like.
The arylthioalkyl at R1 and R12 is that wherein the alkyl moiety may be a linear or branched chain preferably having 1 to 6 carbon atoms, and the aryl moiety is the same as the aryl moiety of the above-mentioned arylalkyl. Examples thereof include phenylthiomethyl, 1-naphthylthiomethyl, 2-naphthylthiomethyl and the like.
The alkylthioalkyl at R1 and R12 is that wherein the alkyl moiety of alkylthio moiety is the same as the above-mentioned alkyl, and the remaining alkyl moiety may be a linear or branched chain preferably having 1 to 6 carbon atoms. Examples thereof include methylthiomethyl, ethylthiomethyl, n-propylthiomethyl, isopropylthiomethyl, n-butylthiomethyl, isobutylthiomethyl, sec-butylthiomethyl, tert-butylthiomethyl and the like.
The arylalkylthioalkyl at R1 and R12 is that wherein the arylalkyl moiety is the same as the above-mentioned arylalky. The remaining alkyl moiety may be a linear or branched chain preferably having 1 to 6 carbon atoms. Examples thereof include benzylthiomethyl, phenethylthiomethyl and the like.
The alkyl moiety of phthalimidoalkyl at R1 and R12 may be a linear or branched chain preferably having 1 to 6 carbon atoms. Examples thereof include phthalimidomethyl, 2-phthalimidoethyl and the like.
The alkenyl at R1 and R12 preferably has 2 to 6 carbon atoms, and examples thereof include vinyl, allyl, 3-butenyl, 5-hexenyl and the like.
The aryl at R2, R11, R14, R15, R19, R20, R21 and R23 the same as the aryl moiety of the above-mentioned arylalkyl, which is preferably phenyl.
The xe2x80x9cAxe2x80x9d in xe2x80x9cxe2x80x94(CH2)lxe2x80x94Axe2x80x9d at R1 and R12 is an N-heterocycle bonded by an N atom, which is exemplified by the following groups. 
wherein R8 and R9 are each hydrogen or show, in combination, a different bond, to form a double bond, R10 is hydrogen, lower alkyl or phenyl, Xxe2x80x2 is xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH(lower alkyl)xe2x80x94, xe2x80x94C(lower alkyl)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(lower alkyl)xe2x80x94 or xe2x80x94Oxe2x80x94, and Yxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(lower alkyl)xe2x80x94.
As used herein, the lower alkyl has 1 to 6 carbon atoms and may be a linear or branched chain. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and the like.
Examples of the N-heterocycle include 2-oxo-1-pyrrolidinyl, 1-oxoisoindolin-2-yl, 2-oxoindolin-1-yl, 2,5-dioxo-1-pyrrolidinyl, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 2,5-dioxo-3-methyl-1-imidazolidinyl, 2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl, 3,5-dioxo-2-methyl-1,2,4-oxadiazolidin-4-yl, 3-methyl-2,4,5-trioxo-1-imidazolidinyl, 2,5-dioxo-3-phenyl-1-imidazolidinyl, 2,6-dioxopiperidino and the like. Preferred are the rings of the formulas (ii), (iii), (vii) and (viii), such as 1-oxoisoindolin-2-yl, 2-oxoindolin-1-yl, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 2,5-dioxo-3-methyl-1-imidazolidinyl, 2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl, more preferred are the rings of the formulas (ii) and (iii), such as 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 2,5-dioxo-3-methyl-1-imidazolidinyl and 2,5-dioxo-3,4,4-trimethyl-1-imidazolidinyl.
The heteroarylalkyl at R2, R11, R14, R15, R19, R20, R21 and R23 is that wherein the alkyl moiety may be a linear or branched chain preferably having 1 to 6 carbon atoms, and the heteroaryl moiety is the same as the heteroaryl moiety of the above-mentioned heteroarylthioalkyl. Examples thereof include 2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 3-(2-pyrrolyl)propyl and the like.
The cycloalkyl at R2 preferably has 3 to 7 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
The cycloalkylalkyl at R2 is that wherein the alkyl moiety may be a linear or branched chain preferably having 1 to 6 carbon atoms, and the cycloalkyl moiety is the same as the above-mentioned cycloalkyl. Examples thereof include cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and the like.
The aromatic hydrocarbon ring at Q1 and Q2 is exemplified by a benzene ring, a naphthalene ring, or an ortho-fused bicyclic hydrocarbon ring having 8 to 10 ring-forming atoms, wherein at least one ring is an aromatic ring (e.g., indene and the like). Preferred is a benzene ring.
The aromatic heterocycle at Q1 and Q2 is exemplified by 5- or 6-membered ring having a carbon atom and 1 to 4 heteroatoms (e.g., oxygen, sulfur or nitrogen), an ortho-fused bicyclic aromatic heterocycle having 8 to 10 ring-forming atoms derived therefrom, particularly, a benzo derivative wherein the heterocycle is fused with benzene ring. Examples of aromatic heterocycle include pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, thiazole, isothiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-triazine, 1,2,3-triazine, 1,3,5-triazine, 1,2,5-oxathiazine, 1,2,6-oxathiazine, benzoxazole, benzothiazole, benzimidazole, thianaphthene, isothianaphthene, benzofuran, isobenzofuran, chromene, isoindole, indole, indazole, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, benzoxazine and the like. Preferred are pyrrole, furan, thiophene, thiazole and pyridine.
The heteroaryl at R16 and R21 is the same as the heteroaryl moiety of the above-mentioned heteroarylthioalkyl, which is preferably pyridyl.
The above-mentioned arylalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, aryl, heteroaryl and heteroarylalkyl are optionally substituted by one or more substituents selected from halogen (e.g., fluorine, chlorine, bromine and iodine), hydroxy, nitro, cyano, trifluoromethyl, lower alkyl (provided that the lower alkyl does not substitute at the alkyl moiety of arylalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl and phthalimidoalkyl), alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, carboxyl, a group of the formula: xe2x80x94COORa wherein Ra is lower alkyl, arylalkyl or aryl, carbamoyl, amino, (lower alkyl)amino, di(lower alkyl)amino, guanidino, hydroxysulfonyloxy, sulfo, arylalkyloxyalkyl and the like.
As used herein, lower alkyl, arylalkyl and aryl are the same as those mentioned above. Alkoxy may be a linear or branched chain preferably having 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. Alkylthio is that wherein the alkyl moiety may be a linear or branched chain preferably having 1 to 6 carbon atoms. Examples thereof include methylthio, ethylthio, n-propylthio, isopropylthio and the like. Acyloxy is alkanoyloxy which may be a linear or branched chain preferably having 2 to 6 carbon atoms. Examples thereof include acetyloxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, hexanoyloxy and the like. Arylalkyloxyalkyl is that wherein the arylalkyl moiety is the same as the above-mentioned arylalkyl, and the remaining alkyl moiety may be a linear or branched chain preferably having 1 to 6 carbon atoms. Examples thereof include benzyloxymethyl, phenethyloxymethyl and the like. The lower alkyl moiety of (lower alkyl)amino and di(lower alkyl)amino may be a linear or branched chain having 1 to 6 carbon atoms. Examples of (lower alkyl)amino include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino and the like. Examples of di(lower alkyl)amino include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, ethylmethylamino, methylpropylamino, butylmethylamino, ethylpropylamino, ethylbutylamino and the like.
The halogen, lower alkyl, alkoxy, alkylthio, acyloxy, arylalkyl, xe2x80x94COORa (Ra is as defined above) and arylalkyloxyalkyl at R13 and R16 are as defined above.
The optionally substituted heterocycle formed by R14 and R15 together with the adjacent nitrogen atom, and the optionally substituted heterocycle formed by R19 and R20 together with the adjacent nitrogen atom is a 4 to 7-membered ring having a carbon atom and at least one nitrogen atom, which may have, in the ring, at least one atom selected from nitrogen, oxygen and sulfur, as a further heteroatom, wherein the carbon atom constituting the ring is optionally substituted by oxo. In addition, an aromatic ring, such as benzene ring and the like, may be fused therewith utilizing the adjacent two carbon atoms constituting these heterocycles. Examples thereof include azetidino, 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, 2-oxo-1-quinazolinyl and the like.
When the heterocycle has a nitrogen atom as a further heteroatom in the ring, such as 1-piperazinyl, lower alkyl (as defined above), arylalkyl (as defined above), and heteroarylalkyl (as defined above), aryl (as defined above), heteroaryl (as defined above), a group of the formula: xe2x80x94COORa (Ra is as defined above) or acyl may be substituted on the nitrogen atom. As used herein, acyl is expressed by xe2x80x94CORa wherein Ra is as defined above.
Preferable examples of optionally substituted heterocycle include 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl wherein the 4-position nitrogen atom is optionally substituted by lower alkyl.
With regard to the formula (I) and the formula (II) of the present invention, a preferable mode is as follows.
(i) R3 is a group of the formula (A) 
wherein Q1 is a benzene ring, m is an integer of 0 to 3, and R13 is guanidino, hydroxysulfonyloxy, sulfo or a group selected from 
wherein n is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R16 is hydroxysulfonyloxy or sulfo, or
(ii) when R3 is a group other than the aforementioned formula (A),
Y should be a group of the formula (B) 
wherein Q2 is a benzene ring, and R18 is a group selected from 
wherein s is an integer of 1 to 5, u is an integer of 1 or 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R21 is aryl, heteroaryl, hydroxysulfonyloxy, sulfo or carboxy, or
Q2 is a furan ring, and R18 is arylalkyloxyalkyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R22 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy.
With regard to the formula (I) and the formula (II) of the present invention, a more preferable mode is as follows.
(i) R3 is a group of the formula (A) 
wherein Q1 is a benzene ring, m is an integer of 0 to 3, and R13 is guanidino, hydroxysulfonyloxy, sulfo or a group selected from 
wherein n is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R16 is hydroxysulfonyloxy or sulfo, and Y is furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, phenyl, alkoxyphenyl, or phenyl substituted by xe2x80x94NR19R20 
wherein R19 and R20 are the same or different and each is alkyl, or
(ii) R3 is alkyl or a group of the formula 
wherein Q1 is a benzene ring, m is an integer of 0 to 3, and R13 is hydrogen, and
Y is a group of the formula (B) 
wherein Q2 is a benzene ring, and R18 is a group selected from 
wherein s is an integer of 1 to 5, u is an integer of 1 or 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R21 is aryl, heteroaryl, hydroxysulfonyloxy, sulfo or carboxy, or
Q2 is a furan ring, and R18 is arylalkyloxyalkyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroaryl or aryl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R22 is hydroxy, hydroxysulfonyloxy, sulfo or carboxy.
With regard to the formula (I) and the formula (II) of the present invention, a particularly preferable mode is as follows.
(a) R3 is a group of the formula 
wherein Q1 is a benzene ring, m is 1, and R13 is guanidino, hydroxysulfonyloxy, sulfo or a group of the formula 
wherein n is an integer of 1 to 5, r is an integer of 1 or 2, R14 and R15 are the same or different and each is hydrogen or alkyl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and
Y is furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, phenyl, alkoxyphenyl, or phenyl substituted by xe2x80x94NR19R20 
wherein R19 and R20 are the same or different and each is alkyl.
(b) R3 is a group of the formula 
wherein Q1 is a benzene ring, m is 1, and R13 is guanidino, hydroxysulfonyloxy, sulfo or a group of the formula 
wherein n is an integer of 1 to 5, r is 1, R14 and R15 are the same or different and each is hydrogen or alkyl, and
Y is furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, phenyl, alkoxyphenyl, or phenyl substituted by xe2x80x94NR19R20 
wherein R19 and R20 are the same or different and each is alkyl.
(c) R3 is alkyl or benzyl and Y is a group of the formula 
wherein Q2 is a benzene ring, and R18 is a group selected from 
wherein s is an integer of 1 to 5, u is an integer of 1 or 2, R19 and R20 are the same or different and each is hydrogen or alkyl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R21 is phenyl or pyridyl.
(d) R3 is alkyl or benzyl and Y is a group of the formula 
wherein Q2 is a benzene ring, and R18 is a group selected from 
wherein s is an integer of 1 to 5, u is 1, R19 and R20 are the same or different and each is hydrogen or alkyl, or R19 and R20 may form, together with the adjacent nitrogen atom, a heterocycle selected from 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl wherein the 4-position nitrogen atom is optionally substituted by lower alkyl, and R21 is phenyl or pyridyl.
(e) R3 is alkyl or benzyl and Y is a group of the formula 
wherein Q2 is a furan ring, and R18 is phenylalkyloxyalkyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R21 are the same or different and each is hydrogen or alkyl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R22 is hydroxy.
(f) R3 is alkyl or benzyl and Y is a group of the formula 
wherein Q2 is a furan ring, and R18 is benzyloxymethyl or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 or 1, R19 and R21 are the same or different and each is hydrogen or alkyl, and R22 is hydroxy.
Another preferable mode of the present invention is as follows.
A preferable example of a group of the formula 
at R3 is a group wherein Q1 is a benzene ring, and R13 is hydrogen, guanidino, hydroxysulfonyloxy or a group of the formula 
wherein n is an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is alkyl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle.
More preferable example is a group wherein Q1 is a benzene ring and R13 is hydrogen.
A preferable example of a group of the formula 
at Y is a group wherein Q2 is a benzene ring or an aromatic heterocycle selected from pyrrole, furan, thiophene, thiazole and pyridine, and R18 is hydrogen or a group selected from 
wherein s and t are the same or different and each is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is alkyl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, R21 is aryl or heteroaryl phenyl, and R22 is hydroxy.
More preferable example is a group wherein Q2 is a benzene ring or an aromatic heterocycle selected from pyrrole, furan, thiophene, thiazole and pyridine, and R18 is hydrogen or a group of the formula 
wherein s is an integer of 1 to 5, u is an integer of 0 to 2, R19 and R20 are the same or different and each is alkyl, or R19 and R20 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle.
The hydroxy-protecting group at X may be, for example, arylalkyl (as defined above), aryl (as defined above), heteroaryl (as defined above), silyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like), 2-tetrahydropyranyl, p-methoxybenzyl, tert-butyl and the like. The arylalkyl, aryl and heteroaryl may have one or more substituents exemplified above. The hydroxy-protecting group is preferably silyl, 2-tetrahydropyranyl, benzyl and the like.
The hydroxamic acid derivative and a pharmacologically acceptable salt thereof represented by the formula (I) may have an asymmetric carbon and can exist as an optically active compound and racemate. The racemate can be resolved into respective optically active compounds by a method known per se. When the hydroxamic acid derivative and a pharmacologically acceptable salt thereof have an additional asymmetric carbon, the compound can exist as a mixture of diastereomers or a single diastereomer, all of which can be separated into respective compounds by a method known per se.
The hydroxamic acid derivative and a pharmacologically acceptable salt thereof can show polymorphism, can exist as two or more tautomers, and can exist as a solvate (e.g., ketone solvate, hydrate and the like).
Therefore, the present invention encompasses all of the above-mentioned stereoisomers, optical isomers, polymorphs, tautomers, solvates, mixtures thereof and the like. The optically active compounds, racemates and diastereomers are also encompassed in the present invention.
The pharmacologically acceptable salts of the hydroxamic acid derivative may be, for example, alkali metal salts (e.g., salt with lithium, sodium, potassium and the like), alkaline earth metal salts (e.g., salt with calcium, magnesium and the like), aluminum salt, ammonium salt, salts with organic base (e.g., salt with triethylamine, morpholine, piperidine, triethanolamine and the like) and the like.
Other pharmacologically acceptable salts may be, for example, inorganic acid addition salts (e.g., salt with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like), organic acid addition salts (e.g., salt with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid and the like), salt with amino acid (e.g., salt with glutamic acid, aspartic acid, hystidine, lysine, arginine and the like) and the like. For crystallization, oxalic acid can be used to give a salt.
The preferable modes of the hydroxamic acid derivative or a pharmacologically acceptable salt thereof of the formula (I) include a hydroxamic acid derivative or a pharmacologically acceptable salt thereof of the formula (I) wherein R1 is phthalimidomethyl, a hydroxamic acid derivative or a pharmacologically acceptable salt thereof of the formula (I) wherein R2 is isobutyl, a hydroxamic acid derivative or a pharmacologically acceptable salt thereof of the formula (I) wherein R3 is benzyl optionally substituted by a substituent selected from guanidino, hydroxysulfonyloxy, sulfo, 
wherein n an integer of 1 to 5, r is an integer of 0 to 2, R14 and R15 are the same or different and each is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R14 and R15 may form, together with the adjacent nitrogen atom, an optionally substituted heterocycle, and R16 is hydroxysulfonyloxy or sulfo, and the like. The preferable compounds including these preferable modes are shown in Examples 1-11, 12, 18, 23, 25, 27, 33, 35, 37, 39, 40, 44, 84, 88, 91, 112, 115, 117, 120, 147, 152, 155, 191, 194 and 245 to be mentioned later.
The production methods of the hydroxamic acid derivative and a pharmacologically acceptable salt thereof of the present invention are shown in the following. 
wherein R11xe2x80x2 is the same as R11 (except hydrogen), R12xe2x80x2 is the same as R1, and R1, R2, R3, X and Y are as defined above.
As shown in the above-mentioned Scheme 1, the hydroxamic acid derivative and a pharmacologically acceptable salt thereof of the present invention can be basically prepared using carboxylic acid (III) as a starting compound and by using amino derivative (IV) to prepare an intermediate compound (IIxe2x80x2) according to the C end activation method in peptide synthesis (see Pepuchidogousei no kiso to jikken, Izumiya et al., Maruzen Shoten, p 91), converting the intermediate compound (IIxe2x80x2) to a succinic acid derivative (IIxe2x80x3) and reacting the succinic acid derivative (IIxe2x80x3) with hydroxylamine: XONH2 wherein X is as defined above. The starting compound, carboxylic acid (III), is described in publications (Japanese Patent Application under PCT laid-open under Kohyo No. 6-506445, JP-A-4-352757, JP-A-7-157470, Japanese Patent Application under PCT laid-open under Kohyo No. 4-502008, JP-A-6-65196, WO96/33968, WO94/21625 and the like), and can be prepared according to a conventional method based on these publications.
The amino derivative (IV) can be produced, for example, by the method to be mentioned later.
Each step is explained in detail in the following.
In Step 1, an intermediate compound (IIxe2x80x2) is prepared by reacting carboxylic acid (III) and amino derivative (IV). Typical methods are shown in the following.
Step 1-1) Method Using Mixed Acid Anhydride
The intermediate compound (IIxe2x80x2) can be obtained by reacting carboxylic acid (III) with isobutyl chlorocarbonate in the presence of an amine base, such as triethylamine, N-methylmorpholine and the like, and reacting the resulting compound with amino derivative (IV). The solvent used is an aprotic solvent such as tetrahydrofuran (THF), methylene chloride, ethyl acetate, N,N-dimethylformamide (DMF) and the like, and the reaction proceeds at a temperature of from xe2x88x9215xc2x0 C. to room temperature.
Step 1-2) Method Using Acid Chloride
The carboxylic acid (III) is reacted with oxalyl chloride or thionyl chloride to give an acid chloride. The solvent used is methylene chloride, or a hydrocarbon solvent such as benzene, toluene and the like, and the reaction proceeds at a temperature of from xe2x88x9215xc2x0 C. to room temperature or under heating. The intermediate compound (IIxe2x80x2) can be obtained by reacting the resulting acid chloride with amino derivative (IV) in the presence of an amine base such as triethylamine, pyridine and the like. The solvent used is an aprotic solvent such as THF, ethyl acetate, DMF, methylene chloride, benzene, toluene and the like, and the reaction proceeds at a temperature of from xe2x88x9215xc2x0 C. to room temperature or under heating.
Step 1-3) Method Using DCC-HOBt Method (Coupling Method)
The intermediate compound (IIxe2x80x2) can be obtained by reacting carboxylic acid (III), amino derivative (IV) and 1-hydroxybenzotriazole (HOBt) with a condensing agent, such as 1,3-dicyclohexylcarbodiimide (DCC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) and the like in the presence of an amine base, such as triethylamine, N-methylmorpholine and the like, at a temperature not higher than room temperature. The solvent used is an aprotic solvent such as THF, methylene chloride, ethyl acetate, DMF, pyridine and the like.
Step 1-4) Method Using Active Ester
The carboxylic acid (III) and a phenol derivative, such as pentafluorophenol and the like, or N-hydroxysuccinimide are reacted with a condensing agent, such as DCC and the like, to give an active ester. An amine base may be used as necessary, where examples thereof include triethylamine, N-methylmorpholine and the like. The solvent used is an aprotic solvent, such as THF, DMF, methylene chloride and the like, and the reaction proceeds at a temperature not higher than room temperature. The intermediate compound (IIxe2x80x2) can be obtained by reacting the resulting active ester with amino derivative (IV). An amine base may be used as necessary, where examples thereof include triethylamine, N-methylmorpholine and the like. The solvent used is an aprotic solvent, such as THF, DMF, methylene chloride and the like, and the reaction proceeds at a temperature not higher than room temperature.
In Step 2, the intermediate compound (IIxe2x80x2) is converted to a succinic acid derivative (IIxe2x80x3). For example, when R11xe2x80x2 can be removed with an acid, such as tert-butyl, the intermediate compound (IIxe2x80x2) is reacted with a hydrogen chloride solution or trifluoroacetic acid to give succinic acid derivative (IIxe2x80x3). The solvent used is an ether solvent, such as 1,4-dioxane and the like or methylene chloride and the like, and the reaction proceeds at a temperature not higher than room temperature.
In Step 3, the succinic acid derivative (IIxe2x80x3) is reacted with hydroxylamine:XONH2, wherein X is as defined above, with or without protection with silyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like), tert-butyl, benzyl, 2-tetrahydropyranyl (Chem. Pharm. Bull. Jpn. 23, 167, 1975) and the like. The reaction conditions are the same as in Step 1. When protected hydroxylamine is used, the hydroxylamine-protecting group can be eliminated, after reaction, under the same deprotection conditions as those generally employed for the deprotection of hydroxy-protecting group.
The intermediate compound (IIxe2x80x2) can be also produced by the method shown in the following Scheme 2. 
wherein R2, R3, R11xe2x80x2, R12xe2x80x2 and Y are as defined above.
In Step 4, carboxylic acid (III) and an amino derivative (V) are reacted to give compound (VI). This step is carried out by a method similar to that used in Step 1.
The amino derivative (V) can be produced, for example, by the method to be mentioned later.
In Step 5, compound (VI) is oxidized to give intermediate compound (IIxe2x80x2). As the oxidation method, exemplified are preferably Moffatt oxidation, Swern oxidation, oxidation using Dess-Martin periodinane, Collins oxidation, oxidation using manganese dioxide and the like. The inert solvent to be used is preferably a halogenated hydrocarbon solvent, such as methylene chloride, chloroform and the like, or an aromatic hydrocarbon solvent, such as benzene, toluene, xylene and the like. While the reaction temperature varies depending on the starting compound, oxidation method and the like to be employed, it is generally from xe2x88x9278xc2x0 C. to 50xc2x0 C. While the reaction time varies depending on the starting compound, oxidation method and the like to be used, it is generally 30 minutes-24 hours.
A desired substituent R1 can be introduced by the use of carboxylic acid (III) having this substituent, according to the method shown in the above-mentioned Scheme 1 or 2, without going through a specific step. In addition, for example, the following method shown in Scheme 3 can be employed. 
wherein R1 is heteroarylthioalkyl, arylthioalkyl, alkylthioalkyl or arylalkylthioalkyl, R23xe2x80x2 is the same as R23 (except hydrogen), and R2, R3, R11xe2x80x2 and Y are as defined above.
In Step 6, carboxylic acid (VII) is used as a starting compound, and intermediate compound (IIxe2x80x2a) is obtained by the method of Step 1 in the above-mentioned Scheme 1. The carboxylic acid (VII) to be the starting compound is described in a publication (JP-A-7-157470), and can be prepared by a conventional method based on this publication.
In Step 7, the substituents R11xe2x80x2 and R23xe2x80x2 of intermediate compound (IIxe2x80x2a) are removed to give a succinic acid derivative (IIxe2x80x3a). For example, when R11xe2x80x2 and R23xe2x80x2 are benzyl, a general hydrogenation reaction is carried out in the presence of a metal catalyst at normal pressure or under pressurization. Examples of the metal catalyst include palladium carbon and palladium black and the like. The solvent may be an ether solvent, such as 1,4-dioxane and the like, an ester solvent, such as ethyl acetate and the like, or an alcohol solvent, such as methanol, ethanol, isopropyl alcohol and the like, and the reaction proceeds from room temperature to under heating.
In Step 8, the succinic acid derivative (IIxe2x80x3a) obtained in Step 7 is subjected to decarboxylation to give a succinic acid derivative (IIxe2x80x3b) which is a monocarboxylic acid. The solvent may be a hydrocarbon solvent such as n-hexane, benzene, toluene and the like. The reaction is carried out in the presence of a tertiary amine, such as N-methylmorpholine, triethylamine and the like, at room temperature or under heating.
In Step 9, the succinic acid derivative (IIxe2x80x3a) obtained in Step 7 is reacted with formaldehyde in the presence of a secondary amine to give succinic acid derivative (IIxe2x80x3c) which is xcex1-exomethylenecarboxylic acid. Examples of the secondary amine include piperidine, diethylamine, morpholine and the like. The reaction is carried out in an alcohol solvent, such as methanol and ethanol and the like, or an amide solvent, such as DMF and the like, from room temperature to under heating.
In Step 10, succinic acid derivative (IIxe2x80x3c) obtained in Step 9 is reacted with arylthiol, heteroarylthiol, alkylthiol or arylalkylthiol as a nucleophilic reagent to give succinic acid derivative (IIxe2x80x2d), wherein the substituent R1 is arylthioalkyl, heteroarylthioalkyl, alkylthioalkyl or arylalkylthioalkyl. This reaction is carried out without solvent or in a halogenated hydrocarbon solvent, such as methylene chloride and the like, an alcohol solvent, such as methanol and the like, or in an amide solvent, such as DMF and the like, from room temperature to under heating.
The amino derivative (IV) and amino derivative (V), which are the starting compounds in schemes 1-3, can be produced by the method shown in the following Scheme 4. 
wherein Axe2x80x2 is an amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl and the like, M is lithium or xe2x80x94MgP1 wherein P1 is halogen such as bromine, chlorine and the like, Yxe2x80x3 is 2-thiazolyl or 2-oxazolyl optionally substituted with lower alkyl or phenyl, and R3 and Y are as defined above.
In Step 11, compound (i) and O,N-dimethylhydroxylamine hydrochloride are reacted in an inert solvent in the presence of a condensing agent and a base to give compound (ii). This step can be performed by the general method described in Jean-Alain Fehrentz et al., Synthesis (1983) p. 676-678.
In Step 12, compound (ii) is reacted with an organometallic compound Yxe2x80x94M to give compound (iii). The inert solvent to be used is preferably an aliphatic hydrocarbon solvent, such as hexane, cyclohexane and the like, ether solvent, such as diethyl ether, tetrahydrofuran and the like, and the like.
The reaction temperature is generally from xe2x88x9278xc2x0 C. to 80xc2x0 C., preferably from xe2x88x9278xc2x0 C. to 40xc2x0 C. The reaction time varies depending on the starting compound, solvent, reaction temperature and the like to be employed. It is generally 15 minutes-24 hours, preferably 15 minutes-10 hours.
In Step 13, the amino-protecting group of compound (iii) is removed to give amino derivative (IV).
When the protecting group Axe2x80x2 is tert-butoxycarbonyl, the protecting group can be removed under acidic conditions using, for example, trifluoroacetic acid, hydrogen chloride-containing dioxane, hydrogen chloride-containing methanol, hydrogen bromide-containing acetic acid and the like. The inert solvent to be used is preferably a halogenated hydrocarbon solvent, such as methylene chloride, chloroform and the like, an ether solvent, such as diethyl ether, tetrahydrofuran, dioxane and the like, an alcohol solvent, such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol and the like, an organic acid, such as acetic acid and the like.
The reaction temperature is generally from 0xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 50xc2x0 C. The reaction time is generally 15 minutes-12 hours, preferably 15 minutes-4 hours.
When the protecting group Axe2x80x2 is benzyloxycarbonyl, it is preferably removed by treating with an acid or by catalytic reduction.
The acid to be used for removal with an acid is preferably trifluoromethanesulfonic acid. The solvent to be used is preferably methylene chloride. The reaction temperature is preferably from 0xc2x0 C. to 50xc2x0 C. and the reaction time is preferably 5 minutes-6 hours.
The catalyst to be used for the method based on catalytic reduction is preferably palladium carbon and palladium black. The solvent to be used is preferably an alcohol solvent, such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol and the like, an ether solvent, such as diethyl ether, tetrahydrofuran, 1,4-dioxane and the like, or an ester solvent, such as ethyl acetate and the like. The hydrogen pressure is generally 1-10 atm, and the reaction temperature is preferably from 0xc2x0 C. to 100xc2x0 C. and the reaction time is preferably 5 minutes-24 hours.
In Step 14, compound (ii) is reduced with a reducing agent, such as lithium aluminum hydride and the like, in an inert solvent to give compound (iv). This step is performed according to the general method described in the above-mentioned Jean-Alain Fehrentz et al., Synthesis (1983) p. 676-678.
In Step 15, (a) compound (iv) is reacted with an organometallic compound Yxe2x80x94M in an inert solvent, or (b) compound (iv) is reacted with trimethylsilyl derivative [Yxe2x80x3xe2x80x94Si(CH3)3] wherein Yxe2x80x3 is 2-thiazolyl or 2-oxazolyl optionally substituted by lower alkyl or phenyl, in an inert solvent to give compound (v).
When compound (v) is produced by Step (a), the method is similar to that used in Step 12.
When compound (v) is produced by Step (b), 2-trimethylsilylthiazole optionally substituted by lower alkyl or phenyl, which is a trimethylsilyl derivative, can be prepared by the method described in Alessandro Dondoni et al., J. Org. Chem. (1988) 53 p. 1748-1761. The 2-trimethylsilyloxazole optionally substituted by lower alkyl or phenyl can be prepared by the method described in Alessandro Dondoni et al., J. Org. Chem. (1987) 52 p. 3413-3420.
When 2-trimethylsilylthiazole optionally substituted by lower alkyl or phenyl is used, the reaction is preferably carried out without solvent or in methylene chloride. The reaction temperature is generally from xe2x88x9240xc2x0 C. to 80xc2x0 C., preferably from xe2x88x9220xc2x0 C. to 40xc2x0 C. While the reaction time varies depending on the starting compound, solvent and reaction temperature to be employed, it is generally 1-48 hours, preferably 1-24 hours.
After the reaction without solvent, the reaction mixture is diluted with THF, and the compound is reacted with tetrabutylammonium fluoride at room temperature for 1-2 hours and post-treated by a conventional method to give the objective compound. When a solvent is used, the solvent is evaporated after the reaction and the above step is followed to give the objective compound.
When 2-trimethylsilyloxazole optionally substituted by lower alkyl or phenyl is used, the reaction is preferably carried out without solvent or in benzene, toluene or xylene. The reaction temperature is generally from 0xc2x0 C. to 150xc2x0 C., preferably from 20xc2x0 C. to 100xc2x0 C. While the reaction time varies depending on the starting compound, solvent, reaction temperature and the like to be employed, it is generally 1-80 hours, preferably 1-50 hours.
After the reaction, the objective compound can be obtained in the same manner as for 2-trimethylsilylthiazole. Alternatively, the compound is reacted with 1-2N hydrochloric acid instead of tetrabutylammonium fluoride for 0.5-2 hours and post-treated by a conventional method to give the objective compound.
In Step 16, the amino-protecting group of compound (v) is removed to give an amino derivative (V), which step can be performed by the method similar to that in Step 13.
The compound (iii) and compound (iv) in Scheme 4 can be also produced by the method shown in the following Scheme 5. 
wherein Z is lower alkyl, such as methyl, ethyl and the like, or arylalkyl, such as benzyl and the like, and Axe2x80x2, M, R3 and Y are as defined above.
In Step 17, compound (i) is reacted with alcohol ZOH in the presence of a condensing agent to give compound (vi). The inert solvent to be used is exemplified by a halogenated hydrocarbon solvent, such as methylene chloride, chloroform and the like, an ester solvent, such as ethyl acetate and the like, and an ether solvent, such as diethyl ether, tetrahydrofuran, 1,4-dioxane and the like, with preference given to methylene chloride and tetrahydrofuran.
As the condensing agent, it is preferably DCC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, diphenylphosphoryl azide and the like.
An acid-eliminating agent may be concurrently used in this reaction. The acid-eliminating agent to be used is preferably an organic amine such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, proton sponge and the like.
The reaction temperature is generally from 0xc2x0 C. to 80xc2x0 C., preferably from 0xc2x0 C. to 40xc2x0 C. While the reaction time varies depending on the starting compound, solvent, reaction temperature and the like to be employed, it is generally 1-48 hours, preferably 1-12 hours.
In Step 18, compound (vi) is reacted with an organometallic compound Yxe2x80x94M to give compound (iii), wherein the method similar to that in Step 12 can be employed.
In Step 19, compound (vi) is reduced with a reducing agent, such as diisobutylaluminum hydride and the like, to give compound (iv). This step can be performed by the method described in Daniel H. Rich et al., J. Org. Chem. (1978) 43 p. 3624-3626.
The organometallic compound Yxe2x80x94M to be used in the above-mentioned reaction can be prepared by reacting a compound of the formula: Yxe2x80x94U, wherein U is hydrogen or halogen and Y is as defined above, with alkyllithium, aryllithium or Grignard reagent in an inert solvent.
Examples of the alkyl lithium to be used include ethyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium and the like. Examples of aryllithium include phenyllithium and the like and examples of Grignard reagent include methylmagnesium bromide and the like. The solvent, reaction temperature and reaction time to be employed are the same as those in Step 12.
The compound (i), which is a starting compound in Schemes 4 and 5, can be prepared by the following method.
The compound (i) can be produced by protecting amino of an amino acid of the formula 
with an amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl and the like (see Pepuchidogousei no kiso to jikken, Izumiya et al., Maruzen Shoten, p. 16).
Any variation in various kinds of substituents, inclusive of R3, and the like is not necessarily applicable only to a specific step, but rather, the step is free of limitation as long as it is performed under conditions that do not influence other functional groups present in chemical formula.
The hydroxamic acid derivative of the present invention thus synthesized can be collected at an optional purity by a known separation and purification method, such as condensation, extraction, chromatography, reprecipitation, recrystallization and the like, which are used as appropriate.
A pharmacologically acceptable salt and solvate of the hydroxamic acid derivative can be produced by a known method. Moreover, various isomers and the like of the hydroxamic acid derivative can be produced by a known method.
The hydroxamic acid derivative and a pharmacologically acceptable salt thereof of the present invention are superior in inhibitory activity of TNF xcex1 production in mammals (e.g., human, dog, cat and the like), and low in toxicity.
Therefore, the hydroxamic acid derivative and a pharmacologically acceptable salt thereof of the present invention are useful as an inhibitor of TNF xcex1 production and can be used effectively for the prophylaxis and treatment of the diseases such as autoimmune diseases and inflammatory diseases (e.g., sepsis, MOF, rheumatoid arthritis, Crohn""s disease, cachexia, myasthenia gravis, systemic lupus erythematosus, asthma, I type diabetes, psoriasis and the like), and the like.
When the hydroxamic acid derivative or a pharmacologically acceptable salt thereof of the present invention is used as a pharmaceutical product, a pharmacologically acceptable carrier and the like are used to give a pharmaceutical composition in the form of granules, tablets, capsules, injections, ointment, eye drop, nose drop, cream, aerosol and the like, which can be administered orally or parenterally. Particularly, since the hydroxamic acid derivative and a pharmacologically acceptable salt thereof are superior in water-soluble property, they are preferably used for producing a water-soluble pharmaceutical composition such as injection, eye drop, nasal drop, infusion and the like.
The above-mentioned preparations contain an effective amount of the hydroxamic acid derivative or a pharmacologically acceptable salt thereof.
While the dose of the hydroxamic acid derivative and a pharmacologically acceptable salt thereof varies depending on the administration route, the disease state, body weight and age of patient, and the like, it can be determined as appropriate according to the object of administration. In general, when they are orally administered to an adult, the dose is 0.01-1,000 mg/kg body weight/day, preferably 0.05-250 mg/kg body weight/day, which is preferably administered once or several times a day.